Pharmaceutically active substances are commonly formulated into dosage forms to aid the delivery of small amounts thereof. The amount of pharmaceutically active substance that will be present in the dosage form can vary from a very small amount such as about 0.5 mg up to larger amounts such as about 1000 mg, depending on the pharmaceutically active substance and the pharmaceutical effective amount thereof. In order to be able to accurately administer these amounts of pharmaceutically active substance, the dosage form often includes pharmaceutical acceptable excipients that perform various functions depending on the dosage form and the mode of action required. These excipients have an effect on the method and rate of delivery of the pharmaceutically active substance to the patient.
Another aspect of pharmaceutical formulations that affects the rate of delivery or the bioavailability of the pharmaceutically active substance is the particle size. This relationship between particle size and bioavailability is well known in the pharmaceutical industry and across a range of pharmaceutical products. In 1979, studies into the effect of crystal size on the bioavailability of Benoxaprofen were conducted (Biomed Mass Spectrom., 1979 April, 6(4), pp 173-8, Wolen R L et al; J. Pharm. Sci., 1979 July, 68(7), pp 850-2, Ridolfo A S et al). J. Pharm. Sci., 1980 April, 69(4), pp 391-4, Schoenwald R D & Stewart P disclose the effect of particle size on the ophthalmic bioavailability of dexamethasone stating that “A statistically significant rank-order correlation was observed between increasing drug levels and decreasing particle size.” Other examples include American Journal of Veterinary Research, 1980 December, 41(12), pp 2095-2101, Shastri S et al; Clinical Pharmacokinetics, 1998 February, 34(2), pp 155-62, Miller D B & Spence J D; Current Med Res Opin, 2000, 16(2), pp 134-8, Guichard J P et al; J. Microencapsul., 2001 May-June, 18(3), pp 359-71, Demirel M et al; and Pharmaceutical Dev Technol, 2004, 9(1), pp 1-13, Rasenick N & Muller B W. Also refer to US 2002035119 A1 Rajiv, M et al; US 2003175338 A1 Manoj, K P et al; WO 03/082241 A3 Kumar, P M et al; WO 03/080056 A2 Teva Pharmaceutical Industries Ltd; and US RE37516 E Grebow, P E et al that discuss the relationship between particle size and bioavailability of the pharmaceutically active substance.
Bioavailability can also be increased with the use of a surfactant or wetting agent. This helps to increase the solubility of the pharmaceutically active substance and thus bioavailability. However, there can be an undesired interaction between the pharmaceutically active substance and the wetting agent. Therefore, it is not always beneficial to use a wetting agent to increase the solubility and/or bioavailability of a pharmaceutically active substance.
Particle sizes of substances can be measured using various commonly available methods such as measurement using light (eg. light-scattering methods or turbidimetric methods), sedimentation methods (eg. pipette analysis using an Andreassen pipette, sedimentation scales, photosedimentometers or sedimentation in a centrifugal force), pulse methods (eg. Coulter counter), or sorting by means of gravitational or centrifugal force.
There are various known methods for the control of the particle size of substances including reduction by comminution or de-agglomeration by milling and/or sieving, or particle size increase by agglomeration through granulation, blending or a mixture thereof. These methods use commonly available equipment and/or methods for the reduction or increase of the particle sizes of material. However, these techniques do not allow for the production of a substance with a very narrow, reproducible and consistent distribution of particle size without the need to reprocess, rework or destroy those particles outside of the required distribution. Thus, these processes can be time consuming and costly if reworking of the material under the desired size is not able to be performed. In those circumstances, it is common for the fine material to be destroyed or reprocessed.
Spray-drying can also be used to achieve particles in a narrow particle size distribution. However, inconsistency of the particle size of the feedstock for this process can cause problems with the apparatus such as blockage of the spray jets.
Multi-stage milling techniques have been used on a limited basis in the past to provide substances, such as those for use in inhalants and steroids, where the median particle size is extremely low, eg. below 5 μm, with steep cut-offs on both ends of the particle size spectrum. These processes have required a step-down reduction of particles from >100 μm to ˜50 μm, then to ˜20 μm and finally to below 5 μm. This last stage is not tightly controlled in that the substance with a median particle size of below 5 μm of its very nature must have a narrow distribution of particle size. However, substances with median particle sizes larger than ˜10 μm but still with a narrow, reproducible and consistent distribution have not been manufactured by these techniques in the past.
Other techniques that have been used to obtain uniform particles in a narrow, reproducible and consistent distribution of particle sizes include layering the pharmaceutically active substance onto carrier particles having uniform particle size or spray-drying to form particles of uniform size distribution. Layering or coating requires further processing in specialised equipment designed for small particles and carrier particles in the size distribution required are not always commercially available. Spray-drying techniques also require specialised equipment and it may not be possible to put the pharmaceutically active substance being handled into a solution to be spray-dried. Otherwise the solvent necessary to dissolve the pharmaceutically active substance may not be available or it may not be acceptable for pharmaceutical use. This can be because the pharmaceutically active substance is not stable in solution and degrades or because the solvent is not totally removed from the final product and its residual presence would be unacceptable to health authorities, thereby making the pharmaceutically active substance, and its resultant pharmaceutical product, unacceptable for registration or administration.
Extrusion and spheronising are combined techniques that can give particles with a uniform size and a narrow, reproducible and consistent distribution of particle size. This combined technique requires the pharmaceutically active substance to be made into a paste-like form that can be extruded. The limitation of this technique is that it is difficult to achieve the production of small particles below 200 μm and is generally used for particles above 0.3 mm (300 μm).